In a phase III trial (INAVO120) reported in The New England Journal of Medicine, Turner et al found that the addition of inavolisib to palbociclib/fulvestrant improved progression-free survival in the first-line treatment of patients with PIK3CA-mutated advanced breast cancer.
Inavolisib is an inhibitor of the α isoform of the p110 catalytic subunit of the phosphatidylinositol 3-kinase complex encoded by PIK3CA that also promotes degradation of mutated p110α.
Study Details
In the multinational double-blind trial, 325 patients enrolled between January 2020 and September 2023 were randomly assigned to receive oral inavolisib at 9 mg once daily (n = 161) or placebo (n = 164)—both with palbociclib at 125 mg once-daily on days 1 to 21 of each 28-day cycle and fulvestrant at 500 mg on days 1 and 15 of cycle 1 and every 28 days thereafter. Administration of trial agents continued until disease progression or unacceptable toxicity.
Patients had hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer with relapse during or within 12 months after completion of adjuvant endocrine therapy. The primary endpoint was investigator-assessed progression-free survival.
Progression-Free Survival
Median follow-up was 21.3 months in the inavolisib group and 21.5 months in the control group. Median progression-free survival was 15.0 months (95% confidence interval [CI] = 11.3–20.5 months) in the inavolisib group vs 7.3 months (95% CI = 5.6–9.3 months) in the control group (hazard ratio [HR] = 0.43, 95% CI = 0.32–0.59, P < .001). Rates at 6, 12, and 18 months were 82.9% vs 55.9%, 55.9% vs 32.6%, and 46.2% vs 21.1%.
At interim analysis, overall survival rates at 6, 12, and 18 months were 97.3% vs 89.9%, 85.9% vs 74.9%, and 73.7% vs 67.5%. The stratified hazard ratio was 0.64, 95% CI = 0.43–0.97, P = .03, which did not meet the predefined boundary for significance of P < .0098. An objective response was observed in 58.4% vs 25.0% of patients.
Adverse Events
The most common adverse events of any grade in the inavolisib group were neutropenia (88.9% vs 90.7% in control group), stomatitis/mucosal inflammation (51.2% vs 26.5%), hyperglycemia (58.6% vs 8.6%), diarrhea (48.1% vs 16.0%), and rash (25.3% vs 17.3%).
The most common grade 3 or 4 adverse events in both groups were neutropenia (80.2% vs 78.4%), thrombocytopenia (14.2% vs 4.3%), and leukopenia (6.8% vs 10.5%). Additional grade 3 or 4 adverse events that were more common in the inavolisib group were hyperglycemia (5.6% vs 0%), stomatitis or mucosal inflammation (5.6% vs 0%), and diarrhea (3.7% vs 0%). No grade 3 or 4 rash was observed.
Adverse events led to discontinuation of any treatment component in 6.8% vs 0.6%. No treatment-related deaths were reported.
The investigators concluded: “In patients with PIK3CA-mutated, hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer, inavolisib plus palbociclib/fulvestrant led to significantly longer progression-free survival than placebo plus palbociclib/fulvestrant, with a greater incidence of toxic effects. The percentage of patients who discontinued any trial agent because of adverse events was low.”
Nicholas C. Turner, MD, PhD, of Royal Marsden Hospital and the Institute of Cancer Research, London, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by F. Hoffmann–La Roche. For full disclosure information of all study authors, visit NEJM.org.
